Numerous drugs are prepared in the form of suspensions for ophthalmic, oral, otic, nasal respiratory topical, and parenteral applications. Formulation of pharmaceutical dosages of water-insoluble drugs as suspensions is frequently hampered by the subsequent formation of cakes resulting from aggregation of the suspended material. Polymeric compounds (e.g. polyvinyl pyrrolidone, polyvinyl alcohol, dextran) are commonly used to stabilize such suspensions. An alternative approach to the preparation of such drugs is to enhance the solubility of the drugs within the formulation by vehicles including emulsions, liposomes, and cyclodextrins. However, certain drugs, in their therapeutic concentrations, are not sufficiently stabilized or solubilized by these methods for the above-mentioned applications.
Topical steroids such as corticosteroids are commonly used for anti-inflammatory therapy of the eye, especially for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea and anterior segment of the globe. Common therapeutic applications for steroids include allergic-conjunctivitis, ache rosacea, superficial punctate keratitis and iritis cyclitis. Steroids also are used to ameliorate inflammation associated with corneal injury due to chemical or thermal burns, or penetration of foreign bodies. Such conditions may result from surgery, injury, allergy or infection to the eye and can cause severe discomfort.
Despite their therapeutic advantages, topical ocular use of corticosteroids is associated with a number of complications, including posterior subcapsular cataract formation, elevation of intraocular pressure, secondary ocular infection, retardation of corneal wound healing, uveitis, mydriasis, transient ocular discomfort and ptosis. Numerous systemic complications also may arise from the topical ocular application of corticosteroids. These complications include adrenal insufficiency, Cushing's syndrome, peptic ulceration, osteoporosis, hypertension, muscle weakness or atrophy, inhibition of growth, diabetes, activation of infection, mood changes and delayed wound healing.
Topical steroids for treating ocular inflammations can be based on soft drugs. Soft drugs, as is known in the art, are designed to provide maximal therapeutic effect and minimal side effects. By one approach, synthesis of a "soft drug" can be achieved by structurally modifying a known inactive metabolite of a known active drug to produce an active metabolite that undergoes a predictable one-step transformation in-vivo back to the parent, (see, U.S. Pat. Nos. 4,996,335 and 4,710,495 for soft steroids) inactive metabolite. "Soft drugs" therefore are biologically active chemical components characterized by predictable in vivo metabolism to non-toxic derivatives after they provide their therapeutic effect.
Pharmaceutical compositions of water-insoluble drugs such as corticosteroids in aqueous suspensions for ocular and other uses must satisfy constraints imposed by physiological compatibilities such as pH, osmolality, and particle size of the suspended steroids. Furthermore, these compositions must meet requirements for preservative efficiency and ease of suspension over extended periods of time.
Therapeutic suspensions of corticosteroids typically employ polymeric compounds such as polyvinyl pyrrolidone ("PVP") and polyvinyl alcohol ("PVA") as suspending agents in concentrations ranging from 0.1 to 10% (U.S. Pat. No. 2,861,920). Combinations of polymeric compounds such as PVP, PVA, sodium carboxymethylcellulose ("CMC"), and dextran, with surface-active agents such as Polysorbate 80, Polysorbate 20, and tyloxapol also have been used to stabilize corticosteroid suspensions intended for ophthalmic, nasal, and otic uses.
The amounts of polymeric compounds and surface active agents must be determined to provide stability to suspensions of corticosteroids. Excessive amounts of polymeric compounds may hamper the antimicrobial effects of preservatives added to the suspension. Also, pharmaceutical ocular and nasal dosages of these suspensions either must be buffered or have an appropriate pH with no buffering capacity. These suspensions also should be isotonic.
Loteprednol etabonate ("LE") is a known soft corticosteroid based on the known inactive metabolite prednisolone acetate of the active drug prednisolone. See U.S. Pat. Nos. 4,996,335 and 4,710,495.
LE is an analog of prednisolone that does not have a 20-keto group attached to the 17.beta.-position. Instead, the 17.beta.-position is occupied with a metabolically-labile ester function. In biological systems, LE is hydrolysed to the inactive carboxylic acid metabolite (PJ-91) that does not bind to glucocorticoid receptors. LE also provides superior safety by reducing the risk of steroid induced cataracts and elevation of intra-ocular pressure. The lability of LE to enzymes located in the blood and/or liver also reduces the likelihood of systemic side effects. LE therefore provides therapeutic advantages over other corticosteroids by providing efficacy similar to its parent compound, namely, prednisolone acetate, with fewer deleterious systemic side effects. Soft steroids have the potential advantage of treating inflammation without inducing elevation of intraocular pressure. In addition, soft steroids can provide the added benefit of a lower tendency to induce cataracts which may result from interaction of corticosteroids with the ocular lens proteins.
Formulation of stable aqueous suspensions of LE for ocular applications and other uses, however, has been hampered by agglomeration of the steroid particles. Unexpectedly, common tonicity agents such as aqueous solutions containing 0.9% NaCl, 0.1% EDTA, or phosphate buffer, even in concentrations as low as 1 mM, can not be employed to provide stable aqueous suspensions of corticosteroids such as LE.
A need therefore exists for aqueous suspensions of corticosteroids such as LE which can be formulated without agglomeration. A further need exists for aqueous suspensions which have therapeutically effective amounts of corticosteroids such as LE but which avoid the problems associated with the steroid suspensions of the prior art.